A vanilloid receptor, a receptor for capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), has been cloned in 1997 and called vanilloid receptor subtype 1 (hereinafter referred to as “TRPV1”) by Caterina et al. (Caterina et al., Nature, 389, 816 (1997)). Located on small unmyelinated nerve fibers (C-fibers) and also on large myelinated nerve fibers (A-fibers), TRPV1 is an ion channel which plays an important role in sensitizing pain stimuli by introducing a strong influx of cations such as calcium and sodium ions into the nerve endings upon activation in response to external or internal stimuli. External stimuli capable of activating TRPV1 are reported to include heat and acids as well as vanilloid compounds (Tominaga et al., Neuron, 21, 531 (1998)). The internal stimuli to TRPV1, on the other hand, are leukotriene metabolites such as 12-hydroperoxyeicosa tetraenoic acid (12-HPETE) (Hwang at al., PNAS, 97, 3655 (2000)), and arachidonic acid derivatives such as anandamide (Premkumar et al., Nature, 408, 985 (2000)).
On the basis of these physiological activities, TRPV1 has attracted intensive attention as an integral controller playing a pivotal role in transferring various external stimuli into nerve cells. According to a report, TRPV1 knock-out mice respond like normal mice to general stimuli, but showed greatly reduced pain response to heat or thermal hyperalgesia (Caterina et al., Science, 288, 306 (2000)).
TRPV1 is expressed mainly in primary sensory neurons (Caterina et al., Nature, 389, 816 (1997)), which are responsible for controlling the functions of the skin, bone, and internal organs such as the bladder, the gastrointestinal tract, the lungs, and so on. In addition, TRPV1 is also distributed in other neurons on the central nervous system, the kidney, the stomach, and T-cells (Nozawa et al., Neuroscience Letter, 2001, 309, 33; Yiangou et al., Lancet (North America Edition), 357, 1338 (2001); Birder et al., PNAS, 98, 13396 (2001)) and throughout the entire body, and plays important roles in cell division and cellular signal control.
Also, associated with the control mechanism of the activity of TRPV1 are acute pain, chronic pain, neuropathic pain, postoperative pain, migraines, arthralgia, neuropathy, neuronal damages, diabetic neuropathy, neurological disorders, neurodermatitis, stroke, bladder hypersensitivity, irritable bowel syndrome, respiratory disorders such as asthma, chronic obstructive pulmonary disease, irritation to the skin, eye, and mucous membranes, itching, fever, reflux esophagitis, gastric duodenal ulcer, inflammatory intestinal diseases, and urge incontinence (Korean Laid-Open Publication No. 2004-0034804), obesity (Pharmacol. Rev., 38, 179 (1986)), and glaucoma (WO07/090,134).
As compounds capable of modulating TRPV1 activity, agonists such as a capsaicin derivative (DA-5018) and resiniferatoxin are used as pain-relief drugs or are under clinical study (Szallasi, J. Med chem., 47, 2717 (2004)), while various TRPV1 antagonists including capsazepine and iodoresiniferatoxin are under pre-clinical studies (WO02/008221, WO03/062209, WO04/055003, WO04/055004, WO04/002983, WO02/016317, WO04/035549, WO04/014871, WO03/099284, WO03/022809, WO02/090326, WO02/072536, WO03/068749, WO04/033435, WO02/076946, WO03/055484, WO03/014064, WO03/080578, WO03/097586, WO03/070247, WO03/029199, WO05/002551, WO05/007648, WO05/016890, WO05/047279, WO06/006740, WO06/006741, WO06/063178, WO06/124753, WO06/063178, WO07/067,619, WO07/067,757, WO07/073,303, WO08/006,481, WO08/007,211, and WO08/018,827).